Coactivators are non-DNA binding proteins that mediate transcriptional activities of nuclear receptors (NRs) and many other transcription factors. More than 400 coactivators have been identified and associated with a wide range of human diseases, including neurological and metabolic disorders, inflammatory diseases, and cancer. Steroid receptor coactivators contain three family members, including SRC-1, SRC-2 and SRC-3, which function cooperatively to regulate many cellular signaling pathways. Taking estrogen receptor positive (ER+) breast cancer as an example, cancer cells can employ a number of mechanisms to overcome selective estrogen receptor modulators (SERMs) to silence the nuclear receptor (NR) activity. Although breast cancer cells can become resistant to endocrine therapies, it is essential for these cancer cells to recruit coactivators to survive. Coactivators also partner with other transcription factors; therefore, small molecule inhibitors (SMIs) that can directly target the overexpressed coactivators and reduce their activity or stability are targets for drug development. In addition, stimulation of coactivators can be beneficial for certain pathological conditions, including cancer, and can also be beneficial for the treatment of metabolic disorders.